JOSE PONTES JUNIOR
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/55 - Laboratório de Urologia, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/55 - Laboratório de Urologia, Hospital das Clínicas, Faculdade de Medicina - Líder
11 resultados
Resultados de Busca
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- The role of microRNAs 371 and 34a in androgen receptor control influencing prostate cancer behavior(2015) LEITE, Katia R. M.; MORAIS, Denis Reis; FLOREZ, Manuel Garcia; REIS, Sabrina T.; ISCAIFE, Alexandre; VIANA, Nayara; MOURA, Caio M.; SILVA, Iran A.; KATZ, Betina S.; PONTES JR., Jose; NESRALLAH, Adriano; SROUGI, MiguelBackground: The molecular mechanisms involved in androgen receptor (AR) signaling pathways are not completely understood, and deregulation of microRNAs (miRNAs) expression may play a role in prostate cancer (PC) development and progression. Methods: The expression levels of miRNA and AR were evaluated with quantitative real-time polymerase chain reaction using frozen tissue from the surgical specimens of 83 patients submitted to radical prostatectomy. The expression level of miRNAs was correlated with prognostic factors and biochemical recurrence during a follow-up period of 45 months. In vitro and in vivo experiments were performed to understand the effect of miRNAs over AR in the context of that seen in a PC model. Results: MiR-371 underexpression correlated with non-organ-confined (pT3) disease (P = 0.009). In vitro transfection of miR-371 reduced the levels of AR by 22% and 28% in LNCaP and PC3 cell lines, respectively, and in kallikrein 3, it was reduced by 51%. PC was induced in Balb/c mice using PC-3M-luc-C6 cells, and animals were treated with 3 local doses of miR-371. Tumor growth evaluated by in vivo imaging after luciferase injection was slower in animals treated with miR-371. To explore further the possible role of miRNAs in the AR pathway, LNCaP cell line was treated with 5 alpha-dihydrotestosterone and flutamide showing alteration in miRNAs expression, especially miR-34a, which was significantly underexpressed after treatment with high doses of 5 alpha-dihydrotestosterone. Conclusion: Our data support a role for miRNAs, especially miR-371 and miR-34a, in the complex disarrangement of AR signaling pathway and in the behavior of PC.
- MMP-9 overexpression due to TIMP-1 and RECK underexpression is associated with prognosis in prostate cancer(2011) REIS, Sabrina Thalita; PONTES-JUNIOR, Jose; ANTUNES, Alberto Azoubel; SOUSA-CANAVEZ, Juliana Moreira de; DALL'OGLIO, Marcos Francisco; PASSEROTTI, Carlo C.; ABE, Daniel Kanda; CRIPPA, Alexandre; CRUZ, Jose Arnaldo Shiomi da; TIMOSZCZUK, Luciana M. S.; SROUGI, Miguel; LEITE, Katia R. M.Background: Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their inhibitors. The purpose of this study was to investigate whether the expression of MMP-9 and its specific inhibitors, TIMP-1 and RECK, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis and clinical outcome in prostate cancer (PC). Methods: MMP-9, TIMP-1, and RECK expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue specimens collected from 79 patients with clinically localized PC submitted to radical prostatectorny (RP). Frozen benign prostatic tissue from another 10 men with prostate cancer, also submitted to RP, was analyzed to determine if the profile of gene expression was maintained. The control group consisted of 11 patients with benign prostate hyperplasia (BPH). Results: In the tumor samples, MMP-9 was overexpressed by 9.2 times, and TIMP-1 and RECK were underexpressed (0.75 and 0.80 times, respectively). Overexpression of MMP-9 was significantly related to PSA levels above 10 ng/mL (p=0.033). In addition, MMP-9 overexpression was related to biochemical recurrence, with a marginal statistical significance (p=0.089). MMP-9 was also overexpressed in benign tissues of patients with PC, as were TIMP-1 and RECK, in contrast to their underexpression in tumor samples. Conclusion: Our results show that MMP-9 is overexpressed and its negative regulators are underexpressed in PC tissue, emphasizing a possible role of MMP-9 in the carcinogenesis process. Additionally, we noticed a relationship between MMP-9 overexpression and increased levels of PSA, an important prognostic factor. In benign tissue adjacent to tumors, the MMP-9 equilibrium is likely maintained because the expression of its negative regulators is preserved.
- Tgf-beta 1 expression as a biomarker of poor prognosis in prostate cancer(2011) REIS, Sabrina Thalita dos; PONTES-JUNIOR, Jose; ANTUNES, Alberto Azoubel; SOUSA-CANAVEZ, Juliana Moreira de; ABE, Daniel Kanda; CRUZ, Jose Arnaldo Shiomi da; DALL'OGLIO, Marcos Francisco; CRIPPA, Alexandre; PASSEROTTI, Carlo Camargo; RIBEIRO-FILHO, Leopoldo A.; VIANA, Nayara Izabel; SROUGI, Miguel; LEITE, Katia Ramos MoreiraOBJECTIVE: To evaluate the correlation between transforming growth factor beta (TGF-beta 1) expression and prognosis in prostate cancer. PATIENTS AND METHODS: TGF-beta 1 expression levels were analyzed using the quantitative real-time polymerase chain reaction to amplify RNA that had been isolated from fresh-frozen malignant and benign tissue specimens collected from 89 patients who had clinically localized prostate cancer and had been treated with radical prostatectomy. The control group consisted of 11 patients with benign prostate hyperplasia. The expression levels of TGF-beta 1 were compared between the groups in terms of Gleason scores, pathological staging, and prostate-specific antigen serum levels. RESULTS: In the majority of the tumor samples, TGF-beta 1 was underexpressed 67.0% of PCa patients. The same expression pattern was identified in benign tissues of patients with prostate cancer. Although most cases exhibited underexpression of TGF-beta 1, a higher expression level was found in patients with Gleason scores >= 7 when compared to patients with Gleason scores <7 (p = 0.002). Among the 26 cases of TGF-beta 1 overexpression, 92.3% had poor prognostic features. CONCLUSIONS: TGF-beta 1 was underexpressed in prostate cancers; however, higher expression was observed in tumors with higher Gleason scores, which suggests that TGF-beta 1 expression may be a useful prognostic marker for prostate cancer. Further studies of clinical specimens are needed to clarify the role of TGF-beta 1 in prostate carcinogenesis.
- miR-29b enhances prostate cancer cell invasion independently of MMP-2 expression(2018) IVANOVIC, Renato F.; VIANA, Nayara I.; MORAIS, Denis R.; SILVA, Iran A.; LEITE, Katia R.; PONTES-JUNIOR, Jose; INOUE, Gustavo; NAHAS, William C.; SROUGI, Miguel; REIS, Sabrina T.Background: The ability to metastasize is one of the most important characteristics of neoplastic cells. An imbalance between the action of some matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs drives the invasion process. Some studies have suggested that MMP-2 is involved in metastasis, while other studies have reported that collagen production by cancer cells might also contribute to motility. However, decreased expression of microRNA-29b (miR-29b), which may control MMP-2 and collagen gene expression, has been shown in prostate cancer (PCa). The objectives of the present study were to clarify whether MMP-2 as well as collagens I and III (encoded by COL1A1 and COL3A1, respectively) are controlled by miR-29b and to determine whether metastasis is altered by this relationship. Methods: PCa DU145 and PC-3 cells were transfected with 100 mu L of OPTI-MEM I containing 100 nmol of miR-29b (or its inhibitor) along with 1.5 mu L of lipofectamine. Positive and negative controls were prepared using the same protocol. MMP-2, COL1A1 and COL3A1 messenger RNA (mRNA) levels were evaluated via real-time polymerase chain reaction (qRT-PCR). For qRT-PCR, 6 x 10(4) cells were used. Invasion studies were conducted with Matrigel assays, which simulate invasion of the extracellular matrix by neoplastic cells. After transfection of 3 x 10(4) cells, invasion was allowed to proceed for 48 h. Invasive cells were counted under an optical microscope. Each experiment was performed in triplicate. Results: MMP-2 mRNA was not expressed in DU145 cells after transfection with miR-29b. After transfection of cells with the miR-29b inhibitor, COL1A1 (p = 0.02) and COL3A1 (p = 0.06) mRNA expression was increased in DU145 cells, and a large number of transfected DU145 and PC3 cells invaded the Matrigel membrane. Conclusions: In vitro studies showed that reducing the amount of miR-29b may lead to higher PCa cell invasion via a process that is independent of MMP-2. Collagen expression, controlled by miR-29b, may facilitate this motility process. Thus, the present study suggests that collagen production plays an active role in metastasis control and restoration of miR-29b levels may decrease metastasis. Altogether, these findings support further exploration of drug therapy targeting this aspect of the metastasis circuit.
- Indoleamine 2,3-dioxygenase expression in the prognosis of the localized prostate cancer(2020) FERREIRA, Janaina Mendes; DELLE, Humberto; CAMACHO, Cleber Pinto; ALMEIDA, Robson Jose; REIS, Sabrina Thalita; MATOS, Yves Silva Teles; LIMA, Amanda M. Ramos; LEITE, Katia Ramos Moreira; PONTES-JUNIOR, Jose; SROUGI, MiguelBackground Indoleamine 2,3-dioxygenase (IDO1) is an enzyme that acts as an immunomodulatory molecule. It is found in several types of cancer where it seems to be associated with tumor escape due to its immunosuppressive mechanisms. However, the role of IDO1 expression in prostate cancer (PC) is unclear. The aim of our study was to evaluate the expression of IDO1 in localized PC and to correlate with the classic prognostic factor and recurrence after surgical treatment. Methods We retrospectively evaluated surgical specimens from 111 patients with localized PC, who underwent radical prostatectomy. Recurrence was defined as a prostate specific antigen (PSA) level exceeding 0.2 ng/mL postoperatively, and the follow-up was 123 months. IDO1 expression was evaluated by immunohistochemistry in 72 cases of which 42 (58%) had biochemical recurrence. Results Lower IDO1 expression was associated with higher Gleason score (p = 0.022) and PSA levels (p = 0.042). The multivariate analyses revealed that the loss of IDO1 and higher PSA were independently associated with biochemical recurrence. The chance of recurrence was increased by 85% in patients with lower IDO1 [OR = 0.15;p = 0.009 CI 95% (0.038-0.633)] and increased by 5.5 times in patients with higher PSA [OR = 5.51;p = 0.012 CI 95% (1.435-21.21)]. The recurrence-free survival curve also demonstrates that lower IDO1 was associated with lower time to biochemical recurrence (p = 0.0004). Conclusion The loss of IDO1 expression was associated with increased chance of biochemical recurrence, higher PSA, and a Gleason score in localized PC.
- Controlling RECK miR21 Promotes Tumor Cell Invasion and Is Related to Biochemical Recurrence in Prostate Cancer(2015) LEITE, Katia R. M.; REIS, Sabrina T.; VIANA, Nayara; MORAIS, Denis R.; MOURA, Caio M.; SILVA, Iran A.; PONTES JR., Jose; KATZ, Betina; SROUGI, MiguelThe search for biomarkers to characterize prostate cancer aggressiveness has been the objective for the majority of researchers involved with the most prevalent tumor in men. MiRNAs are important for the control of many cellular functions and their deregulation is involved with tumor development and progression. To find miRNAs differentially expressed in prostate cancer and their relation to prognostic factors and biochemical recurrence we studied 53 surgical specimens from men who underwent radical prostatectomy, through a microarray analysis using the microarray platform (GeneChip (R) miRNA Array - Affymetrix) with more than 46,000 probes and 847 mature human miRNAs and transcripts. We defined different as an expression level greater or less than 1.1 with p<0.05. The validation study using qRT-PCR had confirmed miR21 as overexpressed in tumor that have recurred with a risk of 2.5. Transfection of miR-21 using lipid based assay in DU145 cell line, showed decrease in expression of RECK resulting in increase in expression of MMP9. Invasion assay with Matrigel showed increase in tumor cell invasion after miR-21 transfection. We conclude that miR-21 overexpression is related to increased biochemical recurrence after surgical treatment of prostate cancer. And the negative control of RECK results in overexpression of MMP9 promotes increasing tumor cell invasion supporting miR-21 as an oncomiR related to aggressiveness in prostate cancer.
- miR-21 may acts as an oncomir by targeting RECK, a matrix metalloproteinase regulator, in prostate cancer(2012) REIS, Sabrina Thalita; PONTES-JUNIOR, Jose; ANTUNES, Alberto Azoubel; DALL'OGLIO, Marcos Francisco; DIP, Nelson; PASSEROTTI, Carlo Camargo; ROSSINI, Guilherme Ayres; MORAIS, Denis Reis; NESRALLAH, Adriano Joao; PIANTINO, Camila; SROUGI, Miguel; LEITE, Katia R.Background: Prognosis of prostate cancer (PCa) is based mainly in histological aspects together with PSA serum levels that not always reflect the real aggressive potential of the neoplasia. The micro RNA (miRNA) mir-21 has been shown to regulate invasiveness in cancer through translational repression of the Metaloproteinase (MMP) inhibitor RECK. Our aim is to investigate the levels of expression of RECK and miR-21 in PCa comparing with classical prognostic factors and disease outcome and also test if RECK is a target of miR-21 in in vitro study using PCa cell line. Materials and methods: To determine if RECK is a target of miR-21 in prostate cancer we performed an in vitro assay with PCa cell line DU-145 transfected with pre-miR-21 and anti-miR-21. To determine miR-21 and RECK expression levels in PCa samples we performed quantitative real-time polymerase chain reaction (qRT-PCR). Results: The in vitro assays showed a decrease in expression levels of RECK after transfection with pre-miR-21, and an increase of MMP9 that is regulated by RECK compared to PCa cells treated with anti-miR-21. We defined three profiles to compare the prognostic factors. The first was characterized by miR-21 and RECK underexpression (N = 25) the second was characterized by miR-21 overexpression and RECK underexpression (N = 12), and the third was characterized by miR-21 underexpression and RECK overexpression (N = 16). From men who presented the second profile (miR-21 overexpression and RECK underexpression) 91.7% were staged pT3. For the other two groups 48.0%, and 46.7% of patients were staged pT3 (p = 0.025). Conclusions: Our results demonstrate RECK as a target of miR-21. We believe that miR-21 may be important in PCa progression through its regulation of RECK, a known regulator of tumor cell invasion.
- Correlation between chromosome 9p21 locus deletion and prognosis in clinically localized prostate cancer(2017) BARROS, Erika Aparecida Felix de; PONTES-JUNIOR, Jose; REIS, Sabrina Thalita; LIMA, Amanda Eunice Ramos; SOUZA, Isida C.; SALGUEIRO, Jose Lucas; FONTES, Douglas; DELLE, Humberto; COELHO, Rafael Ferreira; VIANA, Nayara Izabel; LEITE, Katia Ramos Moreira; NAHAS, William C.; SROUGI, MiguelBackground: Some studies have reported that deletions at chromosome arm 9p occur frequently and represent a critical step in carcinogenesis of some neoplasms. Our aim was to evaluate the deletion of locus 9p21 and chromosomes 3, 7 and 17 in localized prostate cancer (PC) and correlate these alterations with prognostic factors and biochemical recurrence after surgery. Methods: We retrospectively evaluated surgical specimens from 111 patients with localized PC who underwent radical prostatectomy. Biochemical recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/mL and the mean postoperative follow-up was 123 months. The deletions were evaluated using fluorescence in situ hybridization with centromeric and locus-specific probes in a tissue microarray containing 2 samples from each patient. We correlated the occurrence of any deletion with pathological stage, Gleason score, ISUP grade group, PSA and biochemical recurrence. Results: We observed a loss of any probe in only 8 patients (7.2%). The most common deletion was the loss of locus 9p21, which occurred in 6.4% of cases. Deletions of chromosomes 3, 7 and 17 were observed in 2.3%, 1.2% and 1.8% patients, respectively. There was no correlation between chromosome loss and Gleason score, ISUP, PSA or stage. Biochemical recurrence occurred in 83% cases involving 9p21 deletions. Loss of 9p21 locus was significantly associated with time to recurrence (p = 0.038). Conclusions: We found low rates of deletion in chromosomes 3, 7 and 17 and 9p21 locus. We observed that 9p21 locus deletion was associated with worse prognosis in localized PC treated by radical prostatectomy.
- miR-618: possible control over TIMP-1 and its expression in localized prostate cancer(2018) IVANOVIC, Renato F.; VIANA, Nayara I.; MORAIS, Denis R.; MOURA, Caio; SILVA, Iran A.; LEITE, Katia R.; PONTES-JUNIOR, Jose; NAHAS, William C.; SROUGI, Miguel; REIS, Sabrina T.BackgroundThe imbalance between the action of the tissue inhibitors of matrix metalloproteinases (TIMPs) and the matrix metalloproteinases (MMPs) is one component of metastasis physiology. TIMP-1 overrides MMP-9 activity in cancer and might be regulated by miR-618. The aims of this study were to clarify whether TIMP-1 expression is modified by miR-618 and to clarify the effect of miR-618 expression on the invasion of prostate cancer cells. We also studied miR-618 expression in surgical specimens of patients with localized prostate cancer submitted to open radical prostatectomy.MethodsAfter transfection of miR-618 or its antagonist in DU145 cells, qRT-PCR for TIMP-1/MMP-9 and both ELISA and zymography for MMP-9 were performed. Total miRNA was extracted from surgical specimens of PCa, and miR-618 expression was examined for correlations with Gleason score, pathological status and biochemical recurrence.ResultsDU145 cells transfected with miR-618 had a 76% reduction in TIMP-1 expression relative to control cells (p=0.003). miR-618 inhibition reduced MMP-9 expression by 31% (p=0.032) and MMP-9 absorbance evaluated with ELISA assay (p=0.06).Zymography suggested higher MMP-9 activity in DU145 cells transfected with miR-618 than those transfected with miR-618 inhibitor, but the difference was not significant (p=0.55). However, miR-618 expression was lower in surgical specimens of patients with Gleason score>7 (p=0.08) and more advanced disease (p=0.07).ConclusionsIn vitro, miR-618 overexpression decreases TIMP-1 and miR-618 inhibition decreases MMP-9, suggesting that miR-618 might be an oncomiR. However, the analysis of clinical samples of localized prostate cancer revealed an inconsistent pattern, as increased miR-618 expression was associated with lower Gleason score and pathological status. Further studies are needed to address whether miR-618 is a context-dependent miRNA.
- Expression profile of standard and variants forms of CD44 related to prostate cancer behavior(2015) MOURA, Caio M.; PONTES JR., Jose; REIS, Sabrina T.; VIANA, Nayara I.; MORAIS, Denis R.; DIP, Nelson; KATZ, Betina; SROUGI, Miguel; LEITE, Katia R. M.CD44 is a transmembrane glycoprotein and is regarded as a potential marker in various tumors. The aim of our study was to analyze the expression of the standard form of CD44 (CD44s) and its isoforms in localized prostate cancer (PCa), and to correlate these data with the classical prognostic factors and biochemical recurrence. Ninety-four surgical specimens were analyzed in this study. The expression levels of CD44s and all its 9 variants were analyzed by quantitative real time PCR (qRT-PCR). The control group consisted of 14 specimens from patients with benign prostatic hyperplasia. We correlated all the expression profiles with biochemical recurrence, as defined by a PSA > 0.4 ng/mL in a mean follow-up period of 53.3 months. In PCa, CD44s was underexpressed and all the other isoforms were overexpressed. The mean expression level of most variants was higher in patients who had not recurred, and a higher expression of CD44v2 independently correlated with a better recurrence-free survival rate (p=0.045). This variant was also underexpressed in metastatic PCa cell lines. There was no correlation between the expression levels of any of the CD44 isoforms and the classical prognostic factors. We here demonstrated that PCa cases are characterized by a change in the expression of CD44, with a loss of CD44s and an overexpression of all the other CD44 variants. However, during cancer progression we found a loss of expression of all CD44 variants, and a correlation between higher expression of CD44v2 and a better recurrence-free survival rate. The understanding of the CD44 expression patterns in PCa could contribute to its use as a new prognostic marker.